(1) Field of the Invention
The present invention relates to a process for producing one or more substituted iminoamines, in particular β-unsaturated β-iminoamines, in a single reaction comprising reacting one or more primary amines, alkynes, and isonitriles in the presence of a transition metal catalytic complex, preferably a titanium metal catalytic complex such as (N,N-di(pyrrolyl-α-methyl)-N-methylamine)titanium (Ti(NMe2)2(dpma)), under reaction conditions effective for 3-component coupling of the primary amines, alkynes, and isonitriles to produce one or more of the substituted iminoamines.
(2) Description of Related Art
One of the goals of methodology development in organic chemistry is to maximize the molecular complexity of the products which can be obtained in a single synthetic step (See Corey and Cheng, In The Logic of Chemical Synthesis, John Wiley & Sons; New York, (1995)). Coupling simple molecules in a predictable fashion is one means of achieving this goal, and the potential utility of the reaction is greatly increased if three or more molecules can be combined in a single synthetic step. For a brief overview of combinatorial chemistry see Beck-Sickinger and Weber, In Combinatorial Strategies in Biology and Chemistry, John Wiley & Sons; West Sussex, England, (2000). For recent articles on diversity-oriented synthesis see Schrieber, Science 287: 1964-1969 (2000); Spring et al., J. Am. Chem. Soc. 124: 1354-1363 (2002); Ding et al., J. Am. Chem. Soc. 124: 1594-1596 (2002); and Hsieh-Wilson et al., Acc. Chem. Res. 29: 164-170 (1996).
Recently, there has been considerable interest in intermolecular hydroamination of alkynes by primary amines using catalysts incorporating rhodium (Hartung et al., J. Org. Chem. 66: 6339-6343 (2001)), palladium (Kadota et al., J. Org. Chem. 64: 4570-4571 (1999); Yamamoto and Radhakrishnan, Chem. Soc. Rev. 28: 199-207 (1999)), ruthenium (Tokunaga et al., Chem. Int. Ed. 38: 3222-3225 (1999)), lanthanides Li and Marks, J. Am. Chem. Soc. 120: 1757-1771 (1998); Li and Marks, Organometallics 15: 3770-3772 (1996)), actinides (Straub et al., Organometallics 20: 5017-5035 (2001); Haskel et al., Organometallics 15: 3773-3775 (1996); Straub et al., J. Chem. Soc. Dalton Trans. 2541-2546 (1996)), and titanium (Johnson and Bergman, J. Am. Chem. Soc. 123: 2923-2924 (2001); Siebeneicher and Doye, J. Prakt. Chem. Chem. Ztg. 341: 102-106 (2000); Haak et al., Angew. Chem. Int. Ed. 38: 3389-3391 (1999); Bytschkov and Doye, Eur. J. Org. Chem. 4411-4418 (2001); Shi et al., Organometallics 21: 3967-3969 (2001); Ong et al., Organometallics 21: 2839-2841 (2002); Ackermann and Bergman, Org. Lett. 4: 1475-1478 (2002); Doye and Sibeneicher, Eur. J. Org. Chem. 1231-1220 (2002); Heutling and Doye, J. Org. Chem. 67: 1961-1964 (2002); and Haak et al., Eur. J. Org. Chem. 457-463 (2002)). Of particular interest has been the hydroamination of alkynes by primary amines using catalysts incorporating titanium. The titanium-catalyzed hydroamination reactions are often rapid, regioselective, and utilize inexpensive catalysts. More recently, the scope of titanium catalysis was expanded to produce products outside of imines using a variety of titanium catalysts for 1,1-disubstitued-hydrazine hydroamination of alkynes, which generates hydrazones and substituted indoles (Cao et al., Org. Lett. 4: 2853-2866 (2002)(web published on Jul. 26, 2002).
A single-step process for the coupling of three simple molecules via transition metal catalysis such as titanium catalysis to produce highly substituted iminoamines would be particularly desirable because such a process would provide a rapid and inexpensive means for producing useful iminoamine-based pharmaceutical chemicals. The process would also enable large libraries of iminoamine-based products to be constructed from relatively few starting materials which can be screened for useful pharmaceutical chemicals. The present invention provides a process for coupling three molecules to produce highly substituted iminoamines in a single step.